Reference standard and case definitions

Since there is no gold standard to define whether ARI is bacterial, viral, or non-infectious, panel adjudication served as the reference standard [18,23,25,26]. Adjudications were performed by specialists in emergency medicine, infectious diseases, pulmonary medicine, or hospital medicine based on chart reviews performed >28 days after enrollment, and before measuring procalcitonin, the protein panel, or the mRNA panel. Due to the retrospective nature of the adjudications, the diagnostic accuracy of this reference standard is expectedly higher than what might be achieved in real-time by clinical providers. Adjudicators had access to medical records including but not limited to admission notes, consultant notes, discharge summaries, patient-reported symptoms, and laboratory and radiographic results (when clinically indicated). In addition, we performed supplemental microbiological testing including a multiplex viral respiratory pathogen panel (ResPlex V2.0, Qiagen; Respiratory Viral Panel, Luminex; or Respiratory Pathogen Panel, Luminex). Each case was independently adjudicated by two reviewers. If there was discordance with respect to the primary etiology, the case was reviewed by a panel of at least three reviewers. To be categorized as having a viral or bacterial ARI, a subject must have had a compatible clinical syndrome and an identified pathogen. The determination of “noninfectious illness” required an alternative non-infectious diagnosis and negative microbiological testing. Sepsis was defined based on the Sepsis-2 criteria, which requires the presence of systemic inflammatory response syndrome (SIRS) due to infection [24].